Matteo Foschi, Federico De Santis, Francesca Gabriele, Raffaele Ornello, Lucio D’Anna, Andrea Zini, Matteo Paolucci, Stefano Forlivesi, Ludovica Migliaccio, Maria Maddalena Viola, Angelo Cascio Rizzo, Maria Sessa, Ghil Schwarz, Rachele Tortorella, SOMA BANERJEE, Gaurav S. Desai, Kazi Farhad Ahmed, Gabriele Prandin, Leonardo Pantoni, Francesco Mele, Giuseppe Scopelliti, Ilaria Cova, Mariarosaria Valente, Domenico Maisano, Luca Antonelli, Maria Rosaria Bagnato, Giovanni Di Mauro, Francesca Bernocchi, Martina Gaia Di Donna, Barbara Casolla, Perla Mazloum, Corrado Campisi, Agathe Caraux, Laura González-Martín, Ricardo Rigual, Blanca Fuentes, Carlos Hervás-Testal, P. Candelaresi, Vincenzo Andreone, Antonio De Mase, Emanuele Spina, Diana Aguiar de Sousa, Mariana A de Souza, Alberto Fior, Miguel Serôdio, Pietro Caliandro, Aurelia Zauli, Giuseppe Reale, Ahmed Abdelalim, Sandra Ahmed, Samah Ali Ismail, L. Zhang, Tara Latimer, Muhammad Elboghdady, Ahmed Elbassiouny, Tamer Roushdy, Hossam Shokri, Federica Ferrari, Nicola Davide Loizzo, Federico Mazzacane, Maria Guarino, Valentina Barone, Paola Forti, Giuseppe Rinaldi, Marco Vito Rossi, Vincenzo Laterza, Giovanni Frisullo, Pier Andrea Rizzo, Aldobrando Broccolini, Marina Mannino, Valeria Terruso, Marcella Caggiula, Annalisa Rizzo, Ana Catarina Fonseca, Bernardo Nascimento Antunes, Ana M Barbosa, Hrvoje Budinčević, Petra Črnac Žuna, Giovanna Viticchi, Mauro Silvestrini, Lorenzo Barba, Viktoria Musienko, Markus Otto, Piergiorgio Lochner, Benjamin Landau, Sandeep Buddha, Roumeisa Khalil, Maria Grazia Piscaglia, Elena Minguzzi, Marialuisa Zedde, Ahmed Nasreldein, Luisa Vinciguerra, Luís Rufo Costa, Ahmed Elsayed, Mona AlBanna, Laura Tudisco, Maria Giulia Mosconi, Alexandros A. Polymeris, Giovanni Merlino, Simona Sacco
BACKGROUND AND OBJECTIVES: Patients with atrial fibrillation (AF) who experience an ischemic stroke despite oral anticoagulation (OAC) face a high risk of recurrence and bleeding. We aimed to compare 90-day outcomes between patients with and without competing stroke etiologies after a breakthrough ischemic stroke while on OAC for AF. METHODS: ASPERA-R retrospectively enrolled adults (>18 years) with AF who experienced a breakthrough ischemic stroke, defined as either first or recurrent event, occurring on continuous OAC (last intake ≤48 hours), across 35 centers from February 2020 to February 2025. Patients' eligibility required imaging-confirmed ischemic stroke, baseline vessel imaging, and a standardized 90-day follow-up. Patients with inadequate anticoagulant dosing or poor adherence were excluded. Competing etiologies were defined as any additional mechanism coexisting with cardioembolism and plausibly contributing to the index stroke. The primary outcome was 90-day recurrent ischemic stroke; secondary outcomes included modified Rankin Scale shift, myocardial infarction, and vascular and all-cause death. Bleedings were also evaluated. We performed inverse probability weighting to balance baseline covariates and applied Cox or regression models to compare outcomes. RESULTS: = 0.020). Other outcomes did not differ. DISCUSSION: One in 4 patients with AF and breakthrough ischemic stroke on OAC had competing etiologies, most often large artery atherosclerosis. These patients showed higher risk of recurrent stroke, functional dependence, mortality, and bleeding, highlighting the need for development of individualized secondary prevention. Main study limitations include observational retrospective design and incomplete data on on-treatment anticoagulation quality. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT06823466.